Calcimimetics are small molecule drugs that mimic the action of calcium on tissues through allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. Among other uses, calcimimetics are used to treat patients suffering from hyperparathyroidism, often caused by parathyroid cancers and chronic renal failure. A calcimimetic available commercially is (αR)-(−)-α-methyl-N-[3-[3-[trifluoromethylphenyl]propyl]-1-napthalenemethanamine or cinacalcet, sold as the SENSIPAR® brand of cinacalcet in North America and Australia (Amgen Inc., Thousand Oaks, Calif.) and the MIMPARA® brand of cinacalcet in Europe (Amgen Inc., Thousand Oaks, Calif.).
Briefly, calcimimetics are a class of orally active, small molecules that decrease the secretion of parathyroid hormone (PTH) by activating calcium receptors. The secretion of parathyroid hormone is normally regulated by the calcium-sensing receptor. Calcimimetics increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, thereby lowering parathyroid hormone levels within a few hours.
Despite the availability of cinacalcet as a representative member of the calcimimetics, its use in patients is associated with drawbacks. For example, cinacalcet is an inhibitor of CYP2D6, which can increase the blood concentration of drugs metabolized by CYP2D6. Thus, co-administration of cinacalcet with other drugs may cause deleterious drug-drug interactions. In addition, cinacalcet is typically administered at least once daily, whereas a less frequent dose (e.g., once a week dosing) would allow for a more convenient regimen. Further, a calcimimetic with a half-life longer than cinacalcet's 30 to 40 hours would allow for less frequent dosing, providing a more convenient treatment regimen, increased patient compliance, and reduced side effects. Additionally, reducing Cmax would avoid potential hypocalcemia and other risks associated with a high Cmax. Reduction of one or more of these side effects from calcimimetics would enhance their desirability as therapeutic drugs.
The present invention seeks to address these and other needs in the art.